Benzo[b]furans are prevalent in many compounds and natural products that have important biological properties, such as antitumor properties, inhibition of protein phosphatase 1B, 5-HT2 and 5-HT3 antagonist activity, inhibition of 5-Lipoxygenase (5-LO), and anti-fungal properties. Pharmaceutically, these properties are relevant in the treatment for cancer, cardiovascular disease, type 2 diabetes, migraines, dementia, and anxiety.
Most noticeably, perhaps, indole is found as a substituent in the amino acid tryptophan, a precursor for two closely-related hormones: serotonin and melatonin. In addition, many indolic secondary plant metabolites have been found to exhibit potent physiological effects. For instance, indole alkaloids have found widespread medical use (e.g, vincristine in the treatment of leukemia).
Current methods for the synthesis of benzo[b]furans include the dehydrative cyclization of α-(phenoxy)alkyl ketones, cyclofragmentation of oxiranes, acidic dehydration of o-hydroxybenzyl ketones, and base-mediated decarboxylation of o-acylphenoxyacetic acids and esters. These traditional methods are often multistep reactions, limited to a particular substrate, and do not tolerate a variety of functional groups. Similarly, indole syntheses are often multistep and run under harsh conditions, leaving functional groups susceptible. More recently, palladium-based cross-coupling reactions with copper iodide as a cocatalyst have been developed for the synthesis of benzofurans. This is accomplished through a tandem Sonagashira coupling/5-endo-dig cyclization starting from either o-iodophenols or o-ethynylphenols. In comparison to traditional methods for either benzofuran or indole synthesis, these palladium-based protocols offer increased functional group tolerance and improved yields.
Various concerns in the art, however, continue to prompt development of new catalytic systems. In particular, the price of palladium is prohibitive, having risen at least by about 900% in recent years. Further, expensive ligands are required for employment of palladium in reactions of interest. As a result, alternate metals and ligand systems have been the subject of increased study. One such approach, as pertains to benzofuran synthesis, involves copper-based systems. Traditional copper-mediated reactions suffer from drawbacks such as high reaction temperatures, the use of copper salts in near or greater than stoichiometric amounts, sensitivity to functional groups on the aryl halide and irreproducibility. Yet, they remain as the reactions of choice in large- and industrial-scale syntheses. As such, in the past five years, there has been a resurgence in interest in developing mild synthetic methods based on copper-based catalysts as an alternative to palladium(0) catalysts for the formation of aryl-carbon and aryl-heteroatom bonds. In this regard, several research groups have reported copper-based methods for the formation of aryl-carbon, aryl-nitrogen and aryl-oxygen bonds. In addition to being simple and mild, these protocols also accommodate substrates that do not otherwise undergo coupling by palladium catalysis. Moreover, from an economic standpoint and in comparison to palladium, copper-based catalysts are quite attractive. However, several concerns remain, as such catalytic systems have shown limited utility—in particular, with respect to the formation of benzo[b]furans, together with the solvents and reaction conditions used.